Glaucoma is a diverse group of disorders characterized by a damaged optic nerve with resultant loss of peripheral vision and ultimately loss of central vision. In most cases, an elevated intraocular pressure is felt to play a role in the visual loss. Glaucoma is the second leading cause of permanent blindness in the United States and the single leading cause of blindness among African-Americans (Leske, M. C. (1983) American Journal of Epidemiology 118:166-191; Francois, J. (1966) Am J. Ophthalmol 61:652-665; Hoskins, H. D. et al. (1989) Sixth ed. St. Louis: C. V. Mosby) Glaucoma developing between birth and age three is termed primary infantile glaucoma. The majority of cases of glaucoma develop in adulthood after age forty. Juvenile glaucoma occurs later than infantile glaucoma but earlier than the usual adult forms (Hoskins, H. D. et al (1989) Sixth ed. St. Louis: C. V. Mosby).
Infantile glaucoma is thought to be caused by incomplete development of the anterior segment of the eye. In contrast, there are no developmental anomalies associated with the more prevalent adult forms of glaucoma. Children with infantile glaucoma typically have symptoms of tearing, photophobia, corneal clouding and large eyes by the time they reach one year of age.
Juvenile open angle glaucoma occurs after age three (when the eye ceases to grow in response to increased intra-ocular pressure) but before age forty. There are two forms of juvenile glaucoma; one that appears as a late form of infantile glaucoma with similar iridocorneal angle anomalies, and another that has normal angles and is similar to adult primary open angle glaucoma.
The adult onset glaucomas are subdivided by the mechanisms of pressure elevation into closed angle and open angle glaucoma. If the trabecular meshwork (located in the angle between the iris and cornea) is free from mechanical obstruction, the glaucoma is termed primary open angle glaucoma (POAG). Adult primary open angle glaucoma accounts for about 60-70% of all cases of glaucoma (Hoskins, H. D. et al (1989) Sixth ed. St. Louis: C. V. Mosby). Population surveys suggest that the prevalence of primary open angle glaucoma in the general population is between 0.63% and 1.25% (Banks, J. L. K. et al. (1968) British Medical Journal 1:791; Popovic, V. (1982) Acta Ophthalmologica 60:745-758). In these patients, there is an insidious increase in intraocular pressure, usually beginning late in life. The anterior segment of the eye appears normal by examination and there is no identifiable cause of the increased pressure. When damage to the optic nerve or loss of visual field is detected, the patient is diagnosed as having glaucoma. In some forms of adult primary open angle glaucoma with iris hypoplasia (Weatherill, J. R. et al (1969) Br J Ophthalmol 53:433-8; Berg, F. (1932) Acta Ophthalmol 10:568-587; Francois, J. et al (1950) Bull Soc Belge Ophthal 96:665-683; Hambresin, M. L. et al (1946) Societe Francaise d'Ophthalmologie 59:219-223; McCulloch, C. et al (1950) Transcripts of the Canadian Ophthalmologic Society 79-91).
It has been reported that 4-16% of first degree relatives of patients with POAG develop the disease (Phelps, C. D. & Podos, S. M., Glaucoma: In Genetic and Metabolic Eye Diseases (ed. Goldberg, M. F.) 237-259 (Little Brown, Boston, 1974); Miller, S. J. H. & Paterson, G. D., Br. J Ophthalmol 46, 513-522 (1962); and Leighton, D. A., Trans. Ophthalmol. Soc. U.K. 96: 28-32 (1976)) and that 13-47% of POAG patients have a positive family history (Phelps, C. D. & Podos, S. M., Glaucoma: In Genetic and Metabolic Eye Diseases (ed. Goldberg, M. F.) 237-259 (Little Brown, Boston, 1974); and Francois, J. Am. J Ophthalmol. 61, 652-665 (1966)). In addition, there have been reports of the existence of families with clearly heritable open angle glaucoma (Harris, D. Am. J. Ophthalmol. 60: 91-95 (1965); Francois, J. Am. J Ophthalmol. 61: 652-665 (1966); Waardenbeurg, P. J. Genetica 25: 79-129 (1950), Biro, I Ophthalmologica 122:228-238 (1951) and Johnson, A. T. et al., Ophthalmology 100: 524-529 (1993)).
Although these findings raise the possibility that a significant portion of glaucoma may be genetically determined, prior to the instant invention, a glaucoma causing gene had not been identified.